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Gu D, Soepriatna AH, Zhang W, Li J, Zhao J, Zhang X, Shu X, Wang Y, Landis BJ, Goergen CJ, Xie J. Activation of the Hedgehog signaling pathway leads to fibrosis in aortic valves. Cell Biosci 2023; 13:43. [PMID: 36864465 PMCID: PMC9983197 DOI: 10.1186/s13578-023-00980-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 02/03/2023] [Indexed: 03/04/2023] Open
Abstract
BACKGROUND Fibrosis is a pathological wound healing process characterized by excessive extracellular matrix deposition, which interferes with normal organ function and contributes to ~ 45% of human mortality. Fibrosis develops in response to chronic injury in nearly all organs, but the a cascade of events leading to fibrosis remains unclear. While hedgehog (Hh) signaling activation has been associated with fibrosis in the lung, kidney, and skin, it is unknown whether hedgehog signaling activation is the cause or the consequence of fibrosis. We hypothesize that activation of hedgehog signaling is sufficient to drive fibrosis in mouse models. RESULTS In this study, we provide direct evidence to show that activation of Hh signaling via expression of activated smoothened, SmoM2, is sufficient to induce fibrosis in the vasculature and aortic valves. We showed that activated SmoM2 -induced fibrosis is associated with abnormal function of aortic valves and heart. The relevance of this mouse model to human health is reflected in our findings that elevated GLI expression is detected in 6 out of 11 aortic valves from patients with fibrotic aortic valves. CONCLUSIONS Our data show that activating hedgehog signaling is sufficient to drive fibrosis in mice, and this mouse model is relevant to human aortic valve stenosis.
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Affiliation(s)
- Dongsheng Gu
- grid.257413.60000 0001 2287 3919Department of Pediatrics, Indiana University School of Medicine, Wells Center for Pediatric Research, 1040 W. Walnut Street., Indianapolis, IN 46202 USA
| | - Arvin H. Soepriatna
- grid.169077.e0000 0004 1937 2197Purdue University Weldon School of Biomedical Engineering, 206 S. Martin Jischke Drive, Room 3025, West Lafayette, IN 47907 USA ,grid.40263.330000 0004 1936 9094School of Engineering, Center for Biomedical Engineering, Brown University, 184 Hope Street, Providence, RI 02912 USA
| | - Wenjun Zhang
- grid.257413.60000 0001 2287 3919Department of Pediatrics, Indiana University School of Medicine, Wells Center for Pediatric Research, 1040 W. Walnut Street., Indianapolis, IN 46202 USA
| | - Jun Li
- grid.413087.90000 0004 1755 3939Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, 180 Fenglin Road, Shanghai, 200032 China
| | - Jenny Zhao
- grid.257413.60000 0001 2287 3919Department of Pediatrics, Indiana University School of Medicine, Wells Center for Pediatric Research, 1040 W. Walnut Street., Indianapolis, IN 46202 USA ,grid.189504.10000 0004 1936 7558Boston University School of Medicine, 72 E. Concord St., Boston, MA 02118 USA
| | - Xiaoli Zhang
- grid.257413.60000 0001 2287 3919Department of Pediatrics, Indiana University School of Medicine, Wells Center for Pediatric Research, 1040 W. Walnut Street., Indianapolis, IN 46202 USA
| | - Xianhong Shu
- grid.413087.90000 0004 1755 3939Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, 180 Fenglin Road, Shanghai, 200032 China
| | - Yongshi Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
| | - Benjamin J. Landis
- grid.257413.60000 0001 2287 3919Department of Pediatrics, Indiana University School of Medicine, Wells Center for Pediatric Research, 1040 W. Walnut Street., Indianapolis, IN 46202 USA
| | - Craig J. Goergen
- grid.169077.e0000 0004 1937 2197Purdue University Weldon School of Biomedical Engineering, 206 S. Martin Jischke Drive, Room 3025, West Lafayette, IN 47907 USA
| | - Jingwu Xie
- Department of Pediatrics, Indiana University School of Medicine, Wells Center for Pediatric Research, 1040 W. Walnut Street., Indianapolis, IN, 46202, USA. .,Basic and Translational Cancer Review Branch (BTC), Division of Basic and Integrative Biological Sciences (DBIB), Center for Scientific Review, National Institutes of Health, 6701 Rockledge Drive, Bethesda, MD, 20892, USA.
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Kaatz M, Mohr P, Livingstone E, Weichenthal M, Kreuter A, Pföhler C, Leiter U, Ulrich J, Utikal JS, Gutzmer R, Herbst R, Schadendorf D. Effectiveness, Safety and Utilization of Vismodegib for Locally Advanced Basal Cell Carcinoma Under Real-world Conditions: Non-interventional Cohort Study JONAS. Acta Derm Venereol 2022; 102:adv00695. [DOI: 10.2340/actadv.v102.293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Most patients with advanced basal cell carcinomas (BCCs) may not benefit sufficiently from standard treatment comprising surgery and radiation. Vismodegib, an oral selective hedgehog pathway inhibitor, is approved for treatment of patients with locally advanced BCC inappropriate for surgery or radiotherapy, or for patients with symptomatic metastatic BCC. In order to enhance understanding of the effectiveness, safety and utilization of vismodegib in clinical practice in Germany, a non-interventional study, JONAS, was conducted. A total of 53 patients with locally advanced BCC who initiated treatment with vismodegib between 2016 and 2018 were included in the study, which was embedded in the German ADOReg skin cancer registry. Duration of response, the primary endpoint, was 12.4 months, progression-free survival 32.2 months and overall response rate 77.4%. Most adverse events were mild to moderate. Overall, results confirmed previous findings, demonstrating favourable responses and manageable safety of vismodegib in patients with locally advanced BCC in clinical practice.
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Sekulic A, Yoo S, Kudchadkar R, Guillen J, Rogers G, Chang ALS, Guenthner S, Raskin B, Dawson K, Mun Y, Chu L, McKenna E, Lacouture M. Real-world assessment and treatment of locally advanced basal cell carcinoma: Findings from the RegiSONIC disease registry. PLoS One 2022; 17:e0262151. [PMID: 35030185 PMCID: PMC8759646 DOI: 10.1371/journal.pone.0262151] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 12/16/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Limited information is available regarding real-world treatment patterns and their effectiveness and safety in patients with locally advanced basal cell carcinoma, including patients not typically represented in clinical trials. The purpose of the current study was to describe how clinicians diagnose and treat locally advanced basal cell carcinoma in the United States. METHODS This prospective, multicenter, observational registry study included patients with newly diagnosed, Hedgehog pathway inhibitor-naive locally advanced basal cell carcinoma without basal cell carcinoma nevus syndrome (n = 433) treated at 75 US academic and community practices, including dermatology, Mohs surgery, and medical oncology sites. The main outcomes of this study were treatment patterns and associated effectiveness and safety for patients with locally advanced basal cell carcinoma in real-world settings. RESULTS Determination of locally advanced basal cell carcinoma was mainly based on lesion size (79.6% of patients), histopathology (54.3%), extent of involvement (49.0%), and location (46.2%). Within 90 days of determination of locally advanced disease, 115 patients (26.6%) received vismodegib, 251 (58.0%) received surgery/other (non-vismodegib) treatment, and 67 (15.5%) had not yet received treatment (observation). Vismodegib-treated patients had a higher prevalence of high-risk clinical features predictive for locoregional recurrence than those with non-vismodegib treatment or observation. Clinical response rate was 85.1% with vismodegib and 94.9% with non-vismodegib treatment (primarily surgery). The most common adverse events with vismodegib were ageusia/dysgeusia, muscle spasms, alopecia, and weight loss. Rates of cutaneous squamous cell cancers were comparable between vismodegib and non-vismodegib treatment. CONCLUSIONS This prospective observational study offers insight on real-world practice, treatment selection, and outcomes for a nationally representative sample of US patients with locally advanced basal cell carcinoma. For patients with lesions that were not amenable to surgery, vismodegib treatment was associated with effectiveness and safety that was consistent with that observed in clinical trials.
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Affiliation(s)
- Aleksandar Sekulic
- Dermatology, Mayo Clinic, Scottsdale, Arizona, United States of America
- * E-mail:
| | - Simon Yoo
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Ragini Kudchadkar
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Julie Guillen
- UCSF Dermatology and Laser Surgery Center, University of California, San Francisco, California, United States of America
| | - Gary Rogers
- Surgical Dermatology, Tufts New England Medical Center, Boston, Massachusetts, United States of America
| | - Anne Lynn S. Chang
- Dermatology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Scott Guenthner
- Dermatology Center of Indiana/Indiana Clinical Trials Center, Plainfield, Indiana, United States of America
| | - Bernard Raskin
- Dermatology, UCLA School of Medicine, Los Angeles, California, United States of America
| | - Keith Dawson
- Medical Affairs, Genentech, South San Francisco, California, United States of America
| | - Yong Mun
- Biostatistics, Genentech, South San Francisco, California, United States of America
| | - Laura Chu
- Oncology, Genentech, South San Francisco, California, United States of America
| | - Edward McKenna
- Medical Affairs, Genentech, South San Francisco, California, United States of America
| | - Mario Lacouture
- Dermatology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
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Vismodegib improves quality of life in patients with periocular locally advanced basal cell carcinoma: subgroup analysis, STEVIE trial. Eye (Lond) 2022; 36:407-413. [PMID: 33692538 PMCID: PMC8807711 DOI: 10.1038/s41433-021-01493-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/20/2021] [Accepted: 02/23/2021] [Indexed: 02/03/2023] Open
Abstract
OBJECTIVES To evaluate the effect of locally advanced periocular basal cell carcinoma (POLA-BCC) on health-related quality of life (HRQoL) and the benefit of vismodegib treatment among participants in the Safety Events in Vismodegib (STEVIE) trial between 2011 and 2017. METHODS The STEVIE trial was conducted in patients with BCC (all anatomic locations) who were treated with vismodegib in 28-day cycles. Patients completed the Skindex-16, a validated questionnaire for the analysis symptoms, emotions, and functioning, at baseline, on day 1 of cycle 2, on day 1 of cycle 7, and at the end-of-study visit. For the present study, data mining techniques were used to construct an ophthalmic database of the STEVIE study. Skindex-16 scores were compared among patients with POLA-BCC between baseline and follow-up and between patients with POLA-BCC and patients with locally advanced BCC on other sites of the head and face (controls). RESULTS The cohort included 169 patients with POLA-BCC and 428 patients with non-periocular head BCC. Patients with POLA-BCC had a significantly worse overall functioning score at baseline than controls (p = 0.038) and a lower score specifically in activities of daily living (p = 0.001). At the last follow-up, patients with POLA-BCC showed significant improvement in scores for functioning (100%), symptoms (100%), and emotions (75%) relative to baseline. CONCLUSIONS Secondary analysis of the results of the STEVIE trial showed that the HRQoL of patients with POLA-BCC is significantly impaired and can be greatly improved with vismodegib treatment.
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Akhshi T, Shannon R, Trimble WS. The complex web of canonical and non-canonical Hedgehog signaling. Bioessays 2022; 44:e2100183. [PMID: 35001404 DOI: 10.1002/bies.202100183] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/21/2021] [Accepted: 12/30/2021] [Indexed: 12/11/2022]
Abstract
Hedgehog (Hh) signaling is a widely studied signaling pathway because of its critical roles during development and in cell homeostasis. Vertebrate canonical and non-canonical Hh signaling are typically assumed to be distinct and occur in different cellular compartments. While research has primarily focused on the canonical form of Hh signaling and its dependency on primary cilia - microtubule-based signaling hubs - an extensive list of crucial functions mediated by non-canonical Hh signaling has emerged. Moreover, amounting evidence indicates that canonical and non-canonical modes of Hh signaling are interlinked, and that they can overlap spatially, and in many cases interact functionally. Here, we discuss some of the many cellular effects of non-canonical signaling and discuss new evidence indicating inter-relationships with canonical signaling. We discuss how Smoothened (Smo), a key component of the Hh pathway, might coordinate such diverse downstream effects. Collectively, pursuit of questions such as those proposed here will aid in elucidating the full extent of Smo function in development and advance its use as a target for cancer therapeutics.
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Affiliation(s)
- Tara Akhshi
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Rachel Shannon
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - William S Trimble
- Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
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Lear JT, Dummer R, Guminski A. Using drug scheduling to manage adverse events associated with hedgehog pathway inhibitors for basal cell carcinoma. Oncotarget 2021; 12:2531-2540. [PMID: 34966484 PMCID: PMC8711575 DOI: 10.18632/oncotarget.28145] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/10/2021] [Indexed: 11/30/2022] Open
Abstract
Basal cell carcinoma (BCC) is the most common malignancy and form of skin cancer worldwide; advanced BCC, either as locally advanced BCC (laBCC) or metastatic BCC (mBCC), can cause substantial tissue invasion and morbidity. Until the recent availability of the hedgehog pathway inhibitors (HHIs) sonidegib and vismodegib, treatment options for advanced BCC were limited. These agents demonstrate efficacy in patients with laBCC and mBCC; however, the adverse events (AEs) associated with these agents can lead to treatment interruption or discontinuation and reduced quality of life, all of which significantly impact long-term adherence to therapy, which might affect clinical outcome. Given that most AEs are class-related effects, switching HHIs does not appear to lead to a significantly different AE profile, underscoring the importance of maintaining patients on their first HHI. Interrupting treatment of sonidegib and vismodegib does not appear to undermine the efficacy of these agents and is therefore a practical option to manage AEs in order to maintain continued treatment and disease control.
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Affiliation(s)
- John T. Lear
- Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Reinhard Dummer
- Department of Dermatology, University Hospital, University of Zurich, Zurich, Switzerland
- Skin Cancer Center, University Hospital, University of Zurich, Zurich, Switzerland
| | - Alexander Guminski
- Department of Medical Oncology, Royal North Shore Hospital, St Leonards, Australia
- Faculty of Medicine, Sydney Medical School, The University of Sydney, Sydney, Australia
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7
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Tong J, Mitchell B, Roth K, Logan D, Ernst S. Real-World Experience of Vismodegib in Advanced Basal Cell Carcinoma at a Canadian Cancer Center. J Cutan Med Surg 2021; 26:143-148. [PMID: 34663118 DOI: 10.1177/12034754211051234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Vismodegib is a novel Hedgehog pathway inhibitor that has revolutionized the treatment of patients with advanced basal cell carcinoma (BCC) who are poor candidates for surgery or radiation. Few studies have explored the use of vismodegib to facilitate further surgery or radiotherapy, and the optimal treatment duration to balance outcomes with adverse effects. OBJECTIVES To characterize the disease response, progression, and recurrence outcomes of BCC patients, and to report the impact of subsequent therapies. METHODS We performed a retrospective study of 46 adult patients with advanced basal cell carcinoma (aBCC), including both locally advanced (laBCC) and metastatic (mBCC) disease, treated with vismodegib at a single center from 2012 to 2019. RESULTS Thirty-six had laBCC, and 10 had mBCC. Treatment was given over a mean of 21.9 months. Twenty-three (50%) had a complete response (CR), and 19 (41.3%) achieved partial response (PR). Median time to maximal response was 5.3 months. Eleven (23.9%) had resected disease at median 17.2 months, and 11 patients (23.9%) received radiotherapy. Thirty-two (69.6%) experienced progressive disease after achievement of CR or PR. Among 17 CR patients, who stopped treatment, 14 (82.3%) experienced subsequent relapse; 6 (85%) attained a repeat response. Twenty (43.5%) discontinued treatment at least once due to adverse effects. CONCLUSIONS With a response rate of 91%, London Regional Cancer Center's (LRCP)'s experience with vismodegib supports its effectiveness in treatment of aBCC. Moreover, a significant number of patients treated with vismodegib became amenable to surgery or radiotherapy. Toxicity remained an important factor that limited treatment duration.
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Affiliation(s)
- Justin Tong
- 70384 Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
| | - Brandon Mitchell
- 70384 Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
| | - Kathryn Roth
- 70384 Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.,London Regional Cancer Program, London Health Sciences Centre, ON, Canada
| | - Diane Logan
- 70384 Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.,London Regional Cancer Program, London Health Sciences Centre, ON, Canada
| | - Scott Ernst
- 70384 Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.,London Regional Cancer Program, London Health Sciences Centre, ON, Canada
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8
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Tognetti L, Cinotti E, Fiorani D, Couzan C, Cavarretta C, Chazelle M, Labeille B, Pianigiani E, Cevenini G, Perrot JL, Rubegni P. Long‐term therapy of multiple basal cell carcinomas: Clinicodermoscopic score for monitoring of intermittent vismodegib treatment. Dermatol Ther 2019; 32:e13097. [DOI: 10.1111/dth.13097] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 09/09/2019] [Accepted: 09/23/2019] [Indexed: 11/30/2022]
Affiliation(s)
- Linda Tognetti
- Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neuro‐SciencesUniversity of Siena Siena Italy
| | - Elisa Cinotti
- Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neuro‐SciencesUniversity of Siena Siena Italy
| | - Diletta Fiorani
- Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neuro‐SciencesUniversity of Siena Siena Italy
| | - Caroline Couzan
- Dermatology ServiceUniversity Hospital of Saint‐Etienne France
| | - Camilla Cavarretta
- Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neuro‐SciencesUniversity of Siena Siena Italy
| | - Marie Chazelle
- Dermatology ServiceUniversity Hospital of Saint‐Etienne France
| | - Bruno Labeille
- Dermatology ServiceUniversity Hospital of Saint‐Etienne France
| | - Elisa Pianigiani
- Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neuro‐SciencesUniversity of Siena Siena Italy
| | | | - Jean L. Perrot
- Dermatology ServiceUniversity Hospital of Saint‐Etienne France
| | - Pietro Rubegni
- Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neuro‐SciencesUniversity of Siena Siena Italy
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9
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Stevens VW, Stenehjem DD, Patterson OV, Kamauu AWC, Yim YM, Morlock RJ, DuVall SL. Characterization and survival of patients with metastatic basal cell carcinoma in the Department of Veterans Affairs: a retrospective electronic health record review. Arch Dermatol Res 2018; 310:505-513. [DOI: 10.1007/s00403-018-1834-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 04/03/2018] [Accepted: 04/25/2018] [Indexed: 10/17/2022]
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10
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Danhof R, Lewis K, Brown M. Small Molecule Inhibitors of the Hedgehog Pathway in the Treatment of Basal Cell Carcinoma of the Skin. Am J Clin Dermatol 2018; 19:195-207. [PMID: 28887802 DOI: 10.1007/s40257-017-0319-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Basal cell carcinoma (BCC) is the most common type of skin cancer, with rising incidence rates primarily attributed to an aging population and ultraviolet radiation exposure. While the majority of BCCs are localized and respond to standard therapies, a very small minority of these tumors become locally destructive or metastasize. These advanced BCCs may not be amenable to localized treatment with surgery and/or radiation therapy. Most BCCs result from mutations in key receptors in the Hedgehog (HH) signaling pathway. As a result, identification of drugs that inhibit the receptor Smoothened (SMO) in the HH pathway has resulted in novel therapeutic approaches to treating patients with advanced BCC. These HH-pathway inhibiting medications have shown efficacy in clinical trials, and two medications, vismodegib and sonidegib, have received FDA approval. However, several limitations of these drugs have been identified, including treatment-limiting adverse events, drug resistance, and the formation of additional malignancies. This paper aims to summarize the clinical trials leading to the approval of SMO inhibitors, as well as reviewing potential mechanisms driving tumor resistance and the formation of cutaneous squamous cell carcinomas. Strategies to overcome some of these challenges, including the development of drugs that inhibit other downstream targets in the HH pathway, are the subject of ongoing clinical trials.
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Affiliation(s)
- Rebecca Danhof
- Department of Dermatology, Mayo Clinic College of Medicine and Science, Onalaska, WI, USA
| | - Karl Lewis
- Division of Hematology and Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mariah Brown
- Department of Dermatology, University of Colorado School of Medicine, Mail Stop F703, 1665, North Aurora Court, Aurora, CO, 80045, USA.
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11
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Chen L, Aria AB, Silapunt S, Lee HH, Migden MR. Treatment of advanced basal cell carcinoma with sonidegib: perspective from the 30-month update of the BOLT trial. Future Oncol 2018; 14:515-525. [DOI: 10.2217/fon-2017-0457] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Sonidegib, a hedgehog pathway inhibitor, was approved by the US FDA for the treatment of locally advanced basal cell carcinoma which cannot be readily treated with surgery or radiotherapy. The pharmacology and pharmacokinetics of sonidegib will be discussed in this review. Additionally, an in-depth analysis of the BOLT trial and data from the 30-month update will be included. This will serve as an update to a previously published article which reported the 12-month update of the BOLT trial.
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Affiliation(s)
- Leon Chen
- Department of Dermatology, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA
| | - Alexander B Aria
- The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA
| | - Sirunya Silapunt
- Department of Dermatology, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA
| | - Heng-Huan Lee
- Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Michael R Migden
- Departments of Dermatology & Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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12
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Moreno-Arrones OM, Carrillo-Gijon R, Sendagorta E, Rios-Buceta L. Acute generalized exanthematous pustulosis simulating Stevens-Johnson syndrome/toxic epidermal necrolysis associated with the use of vismodegib. JAAD Case Rep 2018; 4:123-125. [PMID: 29387760 PMCID: PMC5789517 DOI: 10.1016/j.jdcr.2017.08.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
| | | | | | - Luis Rios-Buceta
- Department of Dermatology, Ramon y Cajal Hospital, Madrid, Spain
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13
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Sekulic A, Migden MR, Basset-Seguin N, Garbe C, Gesierich A, Lao CD, Miller C, Mortier L, Murrell DF, Hamid O, Quevedo JF, Hou J, McKenna E, Dimier N, Williams S, Schadendorf D, Hauschild A. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer 2017. [PMID: 28511673 DOI: 10.1186/s12885‐017‐3286‐5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration-approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively. ORRs by investigator review were 45% (mBCC) and 60% (laBCC). Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC. METHODS One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity. The primary end point was IRF-assessed ORR. Secondary end points included ORR, duration of response (DOR), progression-free survival, overall survival (OS), and safety. RESULTS At data cutoff (39 months after completion of accrual), 8 patients were receiving the study drug (69 patients in survival follow-up). Investigator-assessed ORR was 48.5% in the mBCC group (all partial responses) and 60.3% in the laBCC group (20 patients had complete response and 18 patients had partial response). ORRs were comparable across patient subgroups, including aggressive histologic subtypes (eg, infiltrative BCC). Median DOR was 14.8 months (mBCC) and 26.2 months (laBCC). Median OS was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort. Adverse events remained consistent with clinical experience. Thirty-three deaths (31.7%) were reported; none were related to vismodegib. CONCLUSIONS This long-term update of the ERIVANCE BCC trial demonstrated durability of response, efficacy across patient subgroups, and manageable long-term safety of vismodegib in patients with advanced BCC. TRIAL REGISTRATION This study was registered prospectively with Clinicaltrials.gov , number NCT00833417 on January 30, 2009.
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Affiliation(s)
- Aleksandar Sekulic
- Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA.
| | - Michael R Migden
- Departments of Dermatology and Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX, 77030, USA
| | - Nicole Basset-Seguin
- Service de Dermatologie, Hôpital Saint-Louis, 1 av claude Vellefaux, 75010, Paris, France
| | - Claus Garbe
- Studienzentrum Dermatologische Onkologie, Universitätsklinikum Tübingen, Liebermeisterstr. 25, 72074, Tübingen, Germany
| | - Anja Gesierich
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany
| | - Christopher D Lao
- University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Chris Miller
- Department of Dermatology, University of Pennsylvania Medical Center, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Laurent Mortier
- Clinique de Dermatologie, Hôpital Claude Huriez, Inserm U1189, Lille, France
| | - Dedee F Murrell
- Dermatology Department, St George Clinical School, University of New South Wales, Grey Street, Sydney, 2217, Australia
| | - Omid Hamid
- The Angeles Clinic and Research Institute, 1818 Wilshire Boulevard, Los Angeles, California, USA
| | | | - Jeannie Hou
- Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA
| | - Edward McKenna
- Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA
| | - Natalie Dimier
- Roche Products Limited, Hexagon Place, 6 Falcon Way, Shire Park, Welwyn Garden City, Hertfordshire, Al7 1TW, UK
| | - Sarah Williams
- Roche Products Limited, Hexagon Place, 6 Falcon Way, Shire Park, Welwyn Garden City, Hertfordshire, Al7 1TW, UK
| | - Dirk Schadendorf
- Klinikum für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Essen, Hufelandstrabe 55, 45147, Essen, Germany
| | - Axel Hauschild
- Universitätsklinikum Schleswig-Holstein, Schittenhelmstr, 7, D-24 105, Kiel, Germany
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14
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Sekulic A, Migden MR, Basset-Seguin N, Garbe C, Gesierich A, Lao CD, Miller C, Mortier L, Murrell DF, Hamid O, Quevedo JF, Hou J, McKenna E, Dimier N, Williams S, Schadendorf D, Hauschild A. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer 2017; 17:332. [PMID: 28511673 PMCID: PMC5433030 DOI: 10.1186/s12885-017-3286-5] [Citation(s) in RCA: 286] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 04/19/2017] [Indexed: 01/16/2023] Open
Abstract
Background In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration–approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively. ORRs by investigator review were 45% (mBCC) and 60% (laBCC). Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC. Methods One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity. The primary end point was IRF-assessed ORR. Secondary end points included ORR, duration of response (DOR), progression-free survival, overall survival (OS), and safety. Results At data cutoff (39 months after completion of accrual), 8 patients were receiving the study drug (69 patients in survival follow-up). Investigator-assessed ORR was 48.5% in the mBCC group (all partial responses) and 60.3% in the laBCC group (20 patients had complete response and 18 patients had partial response). ORRs were comparable across patient subgroups, including aggressive histologic subtypes (eg, infiltrative BCC). Median DOR was 14.8 months (mBCC) and 26.2 months (laBCC). Median OS was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort. Adverse events remained consistent with clinical experience. Thirty-three deaths (31.7%) were reported; none were related to vismodegib. Conclusions This long-term update of the ERIVANCE BCC trial demonstrated durability of response, efficacy across patient subgroups, and manageable long-term safety of vismodegib in patients with advanced BCC. Trial registration This study was registered prospectively with Clinicaltrials.gov, number NCT00833417 on January 30, 2009. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3286-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Aleksandar Sekulic
- Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA.
| | - Michael R Migden
- Departments of Dermatology and Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX, 77030, USA
| | - Nicole Basset-Seguin
- Service de Dermatologie, Hôpital Saint-Louis, 1 av claude Vellefaux, 75010, Paris, France
| | - Claus Garbe
- Studienzentrum Dermatologische Onkologie, Universitätsklinikum Tübingen, Liebermeisterstr. 25, 72074, Tübingen, Germany
| | - Anja Gesierich
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany
| | - Christopher D Lao
- University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Chris Miller
- Department of Dermatology, University of Pennsylvania Medical Center, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Laurent Mortier
- Clinique de Dermatologie, Hôpital Claude Huriez, Inserm U1189, Lille, France
| | - Dedee F Murrell
- Dermatology Department, St George Clinical School, University of New South Wales, Grey Street, Sydney, 2217, Australia
| | - Omid Hamid
- The Angeles Clinic and Research Institute, 1818 Wilshire Boulevard, Los Angeles, California, USA
| | | | - Jeannie Hou
- Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA
| | - Edward McKenna
- Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA
| | - Natalie Dimier
- Roche Products Limited, Hexagon Place, 6 Falcon Way, Shire Park, Welwyn Garden City, Hertfordshire, Al7 1TW, UK
| | - Sarah Williams
- Roche Products Limited, Hexagon Place, 6 Falcon Way, Shire Park, Welwyn Garden City, Hertfordshire, Al7 1TW, UK
| | - Dirk Schadendorf
- Klinikum für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Essen, Hufelandstrabe 55, 45147, Essen, Germany
| | - Axel Hauschild
- Universitätsklinikum Schleswig-Holstein, Schittenhelmstr, 7, D-24 105, Kiel, Germany
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15
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Hepatotoxicity with Vismodegib: An MD Anderson Cancer Center and Research on Adverse Drug Events and Reports Project. Drugs R D 2017; 17:211-218. [PMID: 28063021 PMCID: PMC5318336 DOI: 10.1007/s40268-016-0168-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND On 30 January 2012, the US FDA approved vismodegib (Erivedge®, Genentech, CA, USA) for the management of both metastatic and locally advanced basal cell carcinoma. OBJECTIVE Our objective was to identify evidence of hepatotoxicity with vismodegib in the FDA Adverse Event Reporting System (FAERS) in treated patients in two National Cancer Institute Comprehensive Cancer Centers. METHODS FAERS was searched for reports dated 1 January 2009 through 31 December 2015 using terms including hedgehog pathway and vismodegib and hepatic-related terms such as liver, jaundice, and hepatitis, among others. Disproportionality analyses with estimates of proportional reporting ratio and empirical Bayesian geometric mean were conducted. A comprehensive literature review was conducted, and the clinical databases at the University of Texas MD Anderson Cancer Center and Robert H. Lurie Comprehensive Cancer Center of Northwestern University were searched. RESULTS Two cases of severe liver dysfunction were published (Common Terminology Criteria for Adverse Events [CTCAE] class III), and 94 reports of adverse events (AEs) were detected in FAERS, 35 of which were serious AEs. Safety notifications related to hepatotoxicity have not been issued by the manufacturer or the FDA, although vismodegib is listed in LiverTox and the European Medicines Agency website. CONCLUSION We identified a detectable safety signal for hepatotoxicity for vismodegib within 4 years of FDA approval. Vismodegib should be used in patients with severe liver disease only after careful consideration, and concomitant hepatotoxic medications should be avoided. Rapid dissemination of such safety concerns is expected to result in fewer serious hepatotoxic AEs and more optimal outcomes for patients with cancer receiving vismodegib.
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16
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Dheeraj A, Rigby CM, O'Bryant CL, Agarwal C, Singh RP, Deep G, Agarwal R. Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor-Resistant Basal Cell Carcinoma Cells via Targeting EGFR-MAPK-Akt and Hedgehog Signaling. Photochem Photobiol 2017; 93:999-1007. [PMID: 28120452 DOI: 10.1111/php.12727] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Accepted: 12/02/2016] [Indexed: 02/06/2023]
Abstract
Basal cell carcinoma (BCC) is the most common skin malignancy. Deregulated hedgehog signaling plays a central role in BCC development; therefore, hedgehog inhibitors have been approved to treat locally advanced or metastatic BCC. However, the development of resistance to hedgehog inhibitors is the major challenge in effective treatment of this disease. Herein, we evaluated the efficacy of a natural agent silibinin to overcome resistance with hedgehog inhibitors (Sant-1 and GDC-0449) in BCC cells. Silibinin (25-100 μm) treatment for 48 h strongly inhibited growth and induced death in ASZ001, Sant-1-resistant (ASZ001-Sant-1) and GDC-0449-resistant (ASZ001-GDC-0449) BCC cells. Furthermore, colony-forming ability of ASZ001, ASZ001-Sant-1 and ASZ001-GDC-0449 cells was completely inhibited by silibinin treatment. Molecular analysis showed that silibinin treatment decreased the level of phosphorylated EGFR (Tyrosine 1173) and total EGFR in ASZ001-Sant-1 cells, key signaling molecules responsible for BCC resistance toward hedgehog inhibitors. Further, silibinin treatment decreased the phosphorylated Akt (Serine 473), phosphorylated ERK1/2 (Threonine 202/Tyrosine 204), cyclin D1 and Gli-1 level but increased the SUFU expression in ASZ001-Sant-1-resistant cells. Silibinin treatment of ASZ001-Sant-1-resistant cells also decreased bcl-2 but increased cleaved caspase 3 and PARP cleavage, suggesting induction of apoptosis. Together, these results support silibinin use to target hedgehog inhibitor-resistant BCC cells.
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Affiliation(s)
- Arpit Dheeraj
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.,School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Cynthia M Rigby
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Cindy L O'Bryant
- Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Chapla Agarwal
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.,University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Rana P Singh
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Gagan Deep
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.,Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.,University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO
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17
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Agrawal V, Kim DY, Kwon YG. Hhip regulates tumor-stroma-mediated upregulation of tumor angiogenesis. Exp Mol Med 2017; 49:e289. [PMID: 28127049 PMCID: PMC5291840 DOI: 10.1038/emm.2016.139] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 08/21/2016] [Accepted: 08/22/2016] [Indexed: 12/16/2022] Open
Abstract
Tumor growth is governed by the coordinated action of various types of cells that are present in the tumor environment. Fibroblasts, which constitute a major fraction of the stroma, participate actively in various signaling events and regulate tumor development and metastasis. The Hedgehog (Hh) pathway plays an important role in promoting tumor malignancy via fibroblasts; however, the role of hedgehog interacting protein (hhip; inhibitor of Hh pathway) in tumor growth is poorly understood. Here we implanted B16F10 tumors in hhip+/- mice to study the tumor growth characteristics and the vascular phenotype. Furthermore, the mechanism involved in the observed phenomena was explored to reveal the role of hhip in tumor growth. The tumors that were implanted in hhip+/- mice exhibited accelerated growth and increased tumor angiogenesis. Although we observed a decrease in hypoxia, blood vessels still had abnormal phenotype. We found that increased Hh signaling in tumor fibroblasts induced a high expression of vascular endothelial growth factor (VEGF), which subsequently resulted in an increased proliferation of endothelial cells. Thus, the heterozygous knockdown of hhip in mice could affect Hh signaling in tumor fibroblasts, which could cause the increased production of the growth factor VEGF. This signaling, via a paracrine effect on endothelial cells, increased tumor vascular density.
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Affiliation(s)
- Vijayendra Agrawal
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Dong Young Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Young-Guen Kwon
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
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18
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Fife K, Herd R, Lalondrelle S, Plummer R, Strong A, Jones S, Lear JT. Managing adverse events associated with vismodegib in the treatment of basal cell carcinoma. Future Oncol 2017; 13:175-184. [DOI: 10.2217/fon-2016-0296] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Basal cell carcinomas are the most common form of skin cancer. Some develop into advanced cases not suitable for standard therapy. Vismodegib is the first-in-class oral hedgehog pathway inhibitor (which is dysregulated in 90% of basal cell carcinomas), and has demonstrated efficacy for advanced disease in clinical trials. An UK expert panel met to discuss management strategies for adverse events associated with vismodegib (most commonly taste disturbances, muscle cramps and alopecia). Managing patient expectations and implementing treatment breaks were considered important strategies. Quinine was useful to alleviate muscle cramps. For taste disturbances, food swaps alongside dietician referral were suggested. The experts concluded that these common adverse events can be successfully managed to allow optimum treatment duration of vismodegib.
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Affiliation(s)
- Kate Fife
- Cambridge University Hospitals, Hills Road, Cambridge, CB2 0QQ, UK
| | - Robert Herd
- Western Infirmary & Ross Hall Hospital, 221 Crookston Road, Glasgow, G52 3NQ, UK
| | | | - Ruth Plummer
- Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, High Heaton, Newcastle upon Tyne, NE7 7DN, UK
| | - Amy Strong
- Cambridge University Hospitals, Hills Road, Cambridge, CB2 0QQ, UK
| | - Sarah Jones
- Roche Products Ltd, Hexagon Place, 6 Falcon Way, Welwyn Garden City, AL7 1TW, UK
| | - John T Lear
- Salford Royal Hospital, Stott Lane, Salford, M6 8HD, UK
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19
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Alarcon I, Pasquali P, Malvehy J, Puig S. Tumor regrowth and development of keratinocytic neoplasms in patients under smoothened inhibition: in vivo assessment with reflectance confocal microscopy. Skin Res Technol 2016; 23:283-288. [PMID: 27785832 DOI: 10.1111/srt.12332] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2016] [Indexed: 01/28/2023]
Abstract
BACKGROUND The regrowth of a tumor after complete clinical response and the development of keratinocytic neoplasms while patients are still undergoing continuous vismodegib have stressed the importance of the accurate monitoring to detect recurrences earlier and ensure the best possible outcome. OBJECTIVE The objective of this study was to determine the role of reflectance confocal microscopy (RCM) in monitoring the response of locally advanced basal cell carcinoma (laBCC) to vismodegib and to discard secondary resistance. METHODS Seven patients presenting with nine laBCC, were prospectively included and their response to this drug was assessed by means of clinical examination, dermoscopy, and RCM. The study was conducted at the Melanoma Unit in Hospital Clinic of Barcelona, between June 2012 and March 2013. RESULTS Histologically confirmed lesion 10 mm or larger in diameter for which surgery was contraindicated and radiation therapy was inappropriate. The median patient age was 73 years and the most common histological type was infiltrating BCC. RCM allowed the identification of residual tumor in two lesions and to confirm complete response in the other four cases. Two patients developed new lesions within the tumor bed, they were assessed by RCM showing features of actinic keratosis which were confirmed by histopathology. CONCLUSION The use of in vivo RCM allowed the characterization of the dynamic morphologic changes in tumor response helping to better define partial response and to differentiate it from secondary resistance. Another interesting observation was the recognition of a phenomenon characterized by the development of keratinocytic neoplasms within the tumor bed.
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Affiliation(s)
- I Alarcon
- Melanoma Unit, Dermatology Department, Hospital Clinic, Barcelona, Spain.,Institut de Recerca Biomédica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - P Pasquali
- Department of Dermatology, Pius Hospital de Valls, Valls, Spain
| | - J Malvehy
- Melanoma Unit, Dermatology Department, Hospital Clinic, Barcelona, Spain.,Institut de Recerca Biomédica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.,Universitat de Barcelona, Barcelona, Spain
| | - S Puig
- Melanoma Unit, Dermatology Department, Hospital Clinic, Barcelona, Spain.,Institut de Recerca Biomédica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.,Universitat de Barcelona, Barcelona, Spain
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20
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Chen L, Silapunt S, Migden MR. Sonidegib for the treatment of advanced basal cell carcinoma: a comprehensive review of sonidegib and the BOLT trial with 12-month update. Future Oncol 2016; 12:2095-105. [DOI: 10.2217/fon-2016-0118] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The Hedgehog inhibitors are promising alternative for patients with advanced basal cell carcinoma that are not amenable to radiotherapy or surgery. Sonidegib, also known as LDE225, is an orally available SMO antagonist that was recently approved by the US FDA for the treatment of patients with locally advanced basal cell carcinoma. This article will provide an overview of the pharmacology and pharmacokinetics of sonidegib and in-depth analysis of the BOLT trial with additional data from the 12-month update. The present challenges associated with Hedgehog inhibitors will also be discussed.
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Affiliation(s)
- Leon Chen
- Department of Dermatology, The University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Sirunya Silapunt
- Department of Dermatology, The University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Michael R Migden
- Department of Dermatology, The University of Texas McGovern Medical School at Houston, Houston, TX, USA
- Departments of Dermatology & Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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21
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Chang ALS, Arron ST, Migden MR, Solomon JA, Yoo S, Day BM, McKenna EF, Sekulic A. Safety and efficacy of vismodegib in patients with basal cell carcinoma nevus syndrome: pooled analysis of two trials. Orphanet J Rare Dis 2016; 11:120. [PMID: 27581207 PMCID: PMC5007799 DOI: 10.1186/s13023-016-0506-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 08/23/2016] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Aberrant activation of the Hedgehog (Hh) pathway is a key driver in the pathogenesis of basal cell carcinomas (BCCs), including patients with BCC nevus syndrome (BCCNS). It is unclear whether BCCs arising in patients with BCCNS respond differently to vismodegib than in patients without BCCNS. We examined the best overall response rate (BORR) and adverse events (AEs) of vismodegib in patients with advanced BCC (aBCC) with and without BCCNS. METHODS Patients were treated with vismodegib 150 mg/day in the ERIVANCE BCC trial (ClinicalTrials.gov number, NCT00833417) and the expanded access study (EAS; ClinicalTrials.gov number, NCT01160250). BCCNS diagnosis was based on medical history at the time of enrollment. Metastatic BCC response was evaluated using Response Evaluation Criteria In Solid Tumors, version 1.0 (RECIST v1.0) in both studies. Locally advanced BCC was evaluated by a novel composite end point in ERIVANCE BCC and by RECIST v1.0 in the EAS. Response assessments were performed every 8 weeks in ERIVANCE BCC and every 8-16 weeks in the EAS. Safety assessments (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0) were performed monthly in both trials. Because of described differences in response assessment/schedule, patients with BCCNS were not pooled across trials. Analytic cohorts for BCCNS and sporadic aBCC were created within each trial for comparison using descriptive statistical methods. RESULTS Forty-one patients with BCCNS were included in the study: 22 from ERIVANCE BCC and 19 from the EAS. Investigator-assessed BORR in BCCNS groups ranged from 31 to 81 % in patients with locally advanced BCC (n = 33) and was 50 % in patients with metastatic BCC (n = 6). These results were comparable with the non-BCCNS groups. Incidence and severity of AEs were also comparable between the BCCNS and non-BCCNS groups. Amenorrhea was observed in both patient cohorts and was reversible in two patients who discontinued treatment. CONCLUSION Vismodegib demonstrated comparable efficacy and safety against aBCC in patients with and without BCCNS.
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Affiliation(s)
- Anne Lynn S Chang
- Stanford University, 450 Broadway, Pavilion C, 2nd floor, Redwood City, CA, 94063, USA.
| | - Sarah T Arron
- University of California, San Francisco, 1701 Divisadero Street, Box 0316, San Francisco, CA, 94115, USA
| | - Michael R Migden
- The University of Texas MD Anderson Cancer Center, Unit 1452, 1400 Pressler Street, Houston, TX, 77030, USA
| | - James A Solomon
- Ameriderm Research, 725 West Granada Boulevard, Suite 44, Ormond Beach, FL, 32174, USA.,University of Central Florida, CI6850 Lake Nona Boulevard, Orlando, FL, 32827, USA.,University of Illinois, 506 South Mathews Avenue, Urbana, IL, 61801, USA
| | - Simon Yoo
- Northwestern University, 676 North St. Clair Street, Suite 1600, Chicago, IL, 60611, USA
| | - Bann-Mo Day
- Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
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22
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Lacouture ME, Dréno B, Ascierto PA, Dummer R, Basset-Seguin N, Fife K, Ernst S, Licitra L, Neves RI, Peris K, Puig S, Sokolof J, Sekulic A, Hauschild A, Kunstfeld R. Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma. Oncologist 2016; 21:1218-1229. [PMID: 27511905 PMCID: PMC5061532 DOI: 10.1634/theoncologist.2016-0186] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 06/09/2016] [Indexed: 12/14/2022] Open
Abstract
Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib, a first-in-class small-molecule inhibitor of hedgehog pathway signaling, is approved by regulatory authorities for the treatment of adults who have metastatic BCC or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery and who are not candidates for radiation. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC. Adverse events (AEs) commonly observed in hedgehog pathway inhibitor (HPI)-treated patients include muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and asthenia (fatigue). These AEs are thought to be mechanistically related to inhibition of the hedgehog pathway in normal tissue. Although the severity of the majority of AEs associated with HPIs is grade 1-2, the long-term nature of these AEs can lead to decreased quality of life, treatment interruption, and in some cases discontinuation, all of which might affect clinical outcome. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to HPIs in advanced BCC are described. These observations represent the first step toward the development of mechanism-based preventive and management strategies. Knowledge of these AEs will allow health care professionals to provide appropriate counseling and supportive care interventions, all of which will contribute to improved quality of life and optimal benefit from therapy. IMPLICATIONS FOR PRACTICE The hedgehog pathway inhibitors (HPIs) vismodegib and sonidegib represent a therapeutic breakthrough for patients with advanced basal cell carcinoma. However, the nature of the low-grade adverse events (AEs) commonly observed in HPI-treated patients, including muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and fatigue, can impact clinical outcomes as a result of decreased quality of life and treatment discontinuation. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to administration of HPIs are described, with the goal of enabling health care professionals to provide appropriate counseling and supportive care interventions to their patients.
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Affiliation(s)
| | - Brigitte Dréno
- Department of Dermatology, Hôtel Dieu University Hospital, Nantes, France
| | | | | | | | - Kate Fife
- Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom
| | - Scott Ernst
- Western University London Regional Cancer Program, London, Ontario, Canada
| | | | - Rogerio I Neves
- Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | | | - Susana Puig
- Dermatology Department, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomédiques August Pi I Sunyer, Barcelona, Spain
| | - Jonas Sokolof
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | | | - Axel Hauschild
- Department of Dermatology, University of Kiel, Kiel, Germany
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23
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Dummer R, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, Herd RM, Kaatz M, Loquai C, Stratigos AJ, Schulze HJ, Plummer R, Gogov S, Pallaud C, Yi T, Mone M, Chang ALS, Cornélis F, Kudchadkar R, Trefzer U, Lear JT, Sellami D, Migden MR. The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): A phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol 2016; 75:113-125.e5. [DOI: 10.1016/j.jaad.2016.02.1226] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 02/18/2016] [Accepted: 02/22/2016] [Indexed: 11/16/2022]
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24
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Update on the Use and Treatment of Targeted Molecular Inhibitors for Locally Advanced and Metastatic Non-Melanoma Skin Cancers. Dermatol Surg 2016; 42 Suppl 1:S49-56. [PMID: 26730974 DOI: 10.1097/dss.0000000000000573] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Targeting specific molecular pathway inhibitors has provided a successful approach to the management of selected patients with advanced non-melanoma skin cancer (NMSC). Clinical trials and case studies have provided a rationale for their use in clinical settings. OBJECTIVE To review the current approaches to the use of targeted molecular inhibitors for locally advanced and metastatic squamous cell carcinoma, basal cell carcinoma, and dermatofibrosarcoma protuberans. METHODS Literature review of the current use of molecular inhibitors in the treatment of NMSCs, including case studies, reports, and clinical trials. CONCLUSION The development of molecular pathway inhibitors for the treatment of advanced and metastatic NMSC has increased survival rates and improved clinical outcomes in selected patients with advanced disease.
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Kumar L, Verma S, Kumar S, Prasad DN, Jain AK. Fatty acid vesicles acting as expanding horizon for transdermal delivery. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2016; 45:251-260. [PMID: 26890090 DOI: 10.3109/21691401.2016.1146729] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The body is protected against the external environment by the skin due to its physical barrier nature. Stratum corneum composed of corneocytes surrounded by lipid region performs a major barrier function as it lies in the uppermost area of skin. Alteration in barrier function, increase in permeability, and disorganization of stratum corneum represent diseased skin. Drugs applied to the diseased skin should induce a local effect at the site of application or area close to it along with cutaneous absorption rather than percutaneous absorption. Conventional formulations like ointments, gels, and creams suffer from the drawback of limited local activity. For the enhancement of drug penetration and localization of the drug at the site of action approaches explored are liposomes, niosomes, ethosomes microparticles, and solid lipid nanoparticles. Vesicles composed of fatty acids like oleic acid and linoleic acid represent the new approach used for transdermal penetration and localization. In this review article, our major aim was to explore the applications of fatty acid vesicles for transdermal delivery of various bioactives.
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Affiliation(s)
- Lalit Kumar
- a Department of Pharmaceutics , Shivalik College of Pharmacy , Nangal , Punjab , India.,b I. K. Gujral Punjab Technical University , Jallandhar , Punjab , India
| | - Shivani Verma
- b I. K. Gujral Punjab Technical University , Jallandhar , Punjab , India.,c Department of Pharmaceutics , Rayat Bahra College of Pharmacy , Hoshiarpur , Punjab , India
| | - Sanjeev Kumar
- a Department of Pharmaceutics , Shivalik College of Pharmacy , Nangal , Punjab , India
| | - Deo Nandan Prasad
- d Department of Pharmaceutical Chemistry , Shivalik College of Pharmacy , Nangal , Punjab , India
| | - Amit Kumar Jain
- b I. K. Gujral Punjab Technical University , Jallandhar , Punjab , India.,e Department of Pharmaceutics , Guru Nanak Institute of Pharmacy , Hoshiarpur , Punjab , India
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Gonzalez AC, Ferreira M, Ariel T, Reis SR, Andrade Z, Peixoto Medrado A. Immunohistochemical evaluation of hedgehog signalling in epithelial/mesenchymal interactions in squamous cell carcinoma transformation: a pilot study. J Oral Pathol Med 2015; 45:173-9. [PMID: 26947270 DOI: 10.1111/jop.12346] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/21/2015] [Indexed: 11/28/2022]
Abstract
Precancerous lesions have been studied because of their carcinogenic potential and their association with squamous cell carcinoma (SCC) has been reported. In the tumour microenvironment, the processes of angiogenesis and tissue remodelling are regulated by a family of proteins (Hedgehog) described as being able to modulate epithelial/mesenchymal interactions. The objective of this study was to perform a comparative study of precancerous lesions and SCCs by immunohistochemistry for the presence of Sonic, Gli2, SMO and Patched proteins, members of the Hedgehog pathway. Sixteen cases diagnosed as actinic cheilitis associated with SCC were compared to normal oral mucosa. The sections were subjected to immunohistochemistry and the positively stained cells were counted by morphometric analysis. There was a significant progressive increase in expression of all proteins of the Hedgehog pathway, both in the epithelium and in the connective tissue, when sections of normal mucosa, dysplasia and carcinoma were compared (P < 0.05). Thus, one may suggest that the Hedgehog pathway in tumour transformation influences SCC, and more studies should be conducted to expand the understanding of the role of these proteins in neoplastic transformation.
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Affiliation(s)
- Ana Cristina Gonzalez
- Laboratory of Experimental Pathology, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil
| | - Maira Ferreira
- Basic Science, Bahiana Schoool of Medicine and Public Health, Salvador, Bahia, Brazil
| | - Tamires Ariel
- Laboratory of Experimental Pathology, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil
| | - Sílvia Regina Reis
- Basic Science, Bahiana Schoool of Medicine and Public Health, Salvador, Bahia, Brazil
| | - Zilton Andrade
- Laboratory of Experimental Pathology, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil
| | - Alena Peixoto Medrado
- Basic Science, Bahiana Schoool of Medicine and Public Health, Salvador, Bahia, Brazil
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Migden MR, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, Herd RM, Kudchadkar R, Trefzer U, Gogov S, Pallaud C, Yi T, Mone M, Kaatz M, Loquai C, Stratigos AJ, Schulze HJ, Plummer R, Chang ALS, Cornélis F, Lear JT, Sellami D, Dummer R. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 2015; 16:716-28. [PMID: 25981810 DOI: 10.1016/s1470-2045(15)70100-2] [Citation(s) in RCA: 303] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. METHODS BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053. FINDINGS Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3-4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. INTERPRETATION The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. FUNDING Novartis Pharmaceuticals Corporation.
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Affiliation(s)
- Michael R Migden
- Mohs Surgery Center, Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Alexander Guminski
- Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Ralf Gutzmer
- Department of Dermatology and Allergy, Medizinische Hochschule Hannover, Hannover, Germany
| | - Luc Dirix
- Department of Medical Oncology, Sint-Augustinus Ziekenhuis, Antwerp, Belgium
| | - Karl D Lewis
- Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | | | - Robert M Herd
- Department of Dermatology, Glasgow Royal Infirmary, Glasgow, UK
| | - Ragini Kudchadkar
- Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Sven Gogov
- Oncology Clinical Development, Novartis Pharma, Basel, Switzerland
| | - Celine Pallaud
- Oncology Clinical Development, Novartis Pharma, Basel, Switzerland
| | - Tingting Yi
- Biometrics and Data Management, Oncology Business Unit, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - Manisha Mone
- Oncology Clinical Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - Martin Kaatz
- Department of Dermatology and Allergology, University Hospital Jena, Jena, Germany; SRH Wald-Klinikum Gera, Gera, Germany
| | - Carmen Loquai
- Deparment of Dermatology, University Medical Center Mainz, Mainz, Germany
| | - Alexander J Stratigos
- Deparment of Dermatology, Andreas Sygros Hospital, University of Athens, Athens, Greece
| | | | - Ruth Plummer
- Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, UK
| | - Anne Lynn S Chang
- Deparment of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA
| | - Frank Cornélis
- Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - John T Lear
- Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Dalila Sellami
- Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - Reinhard Dummer
- Universitätsspital Zürich-Skin Cancer Center University Hospital, Zürich, Switzerland
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Basset-Seguin N, Hauschild A, Grob JJ, Kunstfeld R, Dréno B, Mortier L, Ascierto PA, Licitra L, Dutriaux C, Thomas L, Jouary T, Meyer N, Guillot B, Dummer R, Fife K, Ernst DS, Williams S, Fittipaldo A, Xynos I, Hansson J. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol 2015; 16:729-36. [PMID: 25981813 DOI: 10.1016/s1470-2045(15)70198-1] [Citation(s) in RCA: 172] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The Hedgehog pathway inhibitor vismodegib has shown clinical benefit in patients with advanced basal cell carcinoma and is approved for treatment of patients with advanced basal cell carcinoma for whom surgery is inappropriate. STEVIE was designed to assess the safety of vismodegib in a situation similar to routine practice, with a long follow-up. METHODS In this multicentre, open-label trial, adult patients with histologically confirmed locally advanced basal cell carcinoma or metastatic basal cell carcinoma were recruited from regional referral centres or specialist clinics. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and adequate organ function. Patients with locally advanced basal cell carcinoma had to have been deemed ineligible for surgery. All patients received 150 mg oral vismodegib capsules once a day on a continuous basis in 28-day cycles. The primary objective was safety (incidence of adverse events until disease progression or unacceptable toxic effects), with assessments on day 1 of each treatment cycle (28 days) by principal investigator and coinvestigators at the site. Efficacy variables were assessed as secondary endpoints. The safety evaluable population included all patients who received at least one dose of study drug. Patients with histologically confirmed basal cell carcinoma who received at least one dose of study drug were included in the efficacy analysis. An interim analysis was pre-planned after 500 patients achieved 1 year of follow-up. This trial is registered with ClinicalTrials.gov, number NCT01367665. The study is still ongoing. FINDINGS Between June 30, 2011, and Nov 6, 2014, we enrolled 1227 patients. At clinical cutoff (Nov 6, 2013), 499 patients (468 with locally advanced basal cell carcinoma and 31 with metastatic basal cell carcinoma) had received study drug and had the potential to be followed up for 12 months or longer. Treatment was discontinued in 400 (80%) patients; 180 (36%) had adverse events, 70 (14%) had progressive disease, and 51 (10%) requested to stop treatment. Median duration of vismodegib exposure was 36·4 weeks (IQR 17·7-62·0). Adverse events happened in 491 (98%) patients; the most common were muscle spasms (317 [64%]), alopecia (307 [62%]), dysgeusia (269 [54%]), weight loss (162 [33%]), asthenia (141 [28%]), decreased appetite (126 [25%]), ageusia (112 [22%]), diarrhoea (83 [17%]), nausea (80 [16%]), and fatigue (80 [16%]). Most adverse events were grade 1 or 2. We recorded serious adverse events in 108 (22%) of 499 patients. Of the 31 patients who died, 21 were the result of adverse events. As assessed by investigators, 302 (66·7%, 62·1-71·0) of 453 patients with locally advanced basal cell carcinoma had an overall response (153 complete responses and 149 partial responses); 11 (37·9%; 20·7-57·7) of 29 patients with metastatic basal cell carcinoma had an overall response (two complete responses, nine partial responses). INTERPRETATION This study assessed the use of vismodegib in a setting representative of routine clinical practice for patients with advanced basal cell carcinoma. Our results show that treatment with vismodegib adds a novel therapeutic modality from which patients with advanced basal cell carcinoma can benefit substantially. FUNDING F Hoffmann-La Roche.
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Affiliation(s)
| | | | | | | | | | - Laurent Mortier
- University of Lille 2, Lille Regional University Hospital, Hopital Huriez, Lille, France
| | | | - Lisa Licitra
- Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy
| | | | - Luc Thomas
- LYON 1 University-Centre Hospitalier Lyon Sud and Lyons Cancer Research Center (Pr Puisieux), Lyon, France
| | - Thomas Jouary
- Saint Andre Hospital CHU de Bordeaux, Bordeaux, France
| | - Nicolas Meyer
- Paul Sabatier University and Toulouse University Cancer Institute, Toulouse, France
| | | | | | - Kate Fife
- Addenbrooke's Hospital, Cambridge, UK
| | | | | | | | | | - Johan Hansson
- Karolinska University Hospital, Solna, Stockholm, Sweden.
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Yin VT, Merritt H, Esmaeli B. Targeting EGFR and sonic hedgehog pathways for locally advanced eyelid and periocular carcinomas. World J Clin Cases 2014; 2:432-8. [PMID: 25232546 PMCID: PMC4163765 DOI: 10.12998/wjcc.v2.i9.432] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Revised: 07/24/2014] [Accepted: 08/27/2014] [Indexed: 02/05/2023] Open
Abstract
For patients with metastatic or locally advanced eyelid and periocular carcinoma not amenable to surgical excision, targeted therapies have shown efficacy with better tolerability compared to cytotoxic chemotherapy. Overexpression of epithelial growth factor receptor was found in squamous cell carcinomas. Vismodegib targets the mutation in the hedgehog pathway identified in basal cell carcinoma and basal cell nevus syndrome. Targeted therapies provide a novel and potentially effective treatment alternative for patients with eyelid carcinoma not amendable for surgery, including those with metastatic, locally advanced disease, advanced age, and significant comorbidities. High cost, need for long-term treatment, and toxicity are relative limitations.
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Potential smoothened inhibitor from traditional Chinese medicine against the disease of diabetes, obesity, and cancer. BIOMED RESEARCH INTERNATIONAL 2014; 2014:873010. [PMID: 25136636 PMCID: PMC4127221 DOI: 10.1155/2014/873010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 02/15/2014] [Indexed: 01/30/2023]
Abstract
Nowadays, obesity becomes a serious global problem, which can induce a series of diseases such as type 2 diabetes mellitus, cancer, cardiovascular disease, metabolic syndrome, and stoke. For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis. For this reason, smoothened homologue (Smo) protein had been indicated as the drug target. In addition, the small-molecule Smo inhibitor had also been used in oncology clinical trials. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as Smo inhibitor from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), have displayed higher potent binding affinities than the positive control, LY2940680, in the docking simulation. After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain. Hence, we propose precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.
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31
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Ochs MF, Farrar JE, Considine M, Wei Y, Meshinchi S, Arceci RJ. Outlier Analysis and Top Scoring Pair for Integrated Data Analysis and Biomarker Discovery. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2014; 11:520-32. [PMID: 26356020 PMCID: PMC4156935 DOI: 10.1109/tcbb.2013.153] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Pathway deregulation has been identified as a key driver of carcinogenesis, with proteins in signaling pathways serving as primary targets for drug development. Deregulation can be driven by a number of molecular events, including gene mutation, epigenetic changes in gene promoters, overexpression, and gene amplifications or deletions. We demonstrate a novel approach that identifies pathways of interest by integrating outlier analysis within and across molecular data types with gene set analysis. We use the results to seed the top-scoring pair algorithm to identify robust biomarkers associated with pathway deregulation. We demonstrate this methodology on pediatric acute myeloid leukemia (AML) data. We develop a biomarker in primary AML tumors, demonstrate robustness with an independent primary tumor data set, and show that the identified biomarkers also function well in relapsed pediatric AML tumors.
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Affiliation(s)
- Michael F. Ochs
- Department of Mathematics and Statistics, The College of New Jersey, Ewing, NJ, USA
| | - Jason E. Farrar
- College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | | | - Yingying Wei
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | | | - Robert J. Arceci
- Ronald A. Matricaria Institute of Molecular Medicine, Phoenix Children's Hospital, Phoenix, AZ, USA
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Dessinioti C, Plaka M, Stratigos AJ. Vismodegib for the treatment of basal cell carcinoma: results and implications of the ERIVANCE BCC trial. Future Oncol 2014; 10:927-36. [DOI: 10.2217/fon.14.50] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
ABSTRACT: The need for effective treatment of patients with locally advanced or metastatic basal cell carcinoma (BCC), in conjunction with major advances in the elucidation of the molecular basis of this tumor has led to the advent of new targeted therapies – namely, hedgehog inhibitors. The rationale for their use in patients with advanced BCC is based on their inhibitory effect on the hedgehog pathway, which is aberrantly activated in BCCs due to mutations of its primary components, PTCH1 and SMO genes. Vismodegib (GDC-0449) is an orally bioavailable hedgehog pathway inhibitor that selectively inhibits SMO. The ERIVANCE BCC study is a Phase II, international, multicenter clinical trial evaluating the efficacy and safety of vismodegib 150 mg once daily in patients with locally advanced or metastatic BCC. Vismodegib has been approved for the treatment of adult patients with metastatic BCC, or with locally advanced BCC that has recurred following surgery or who are not candidates for surgery or radiation therapy. This article will outline the rationale, design and available results from the ERIVANCE BCC study and discuss the clinical implications of vismodegib in the management of patients with BCC. Challenges regarding vismodegib use include the recurrence of BCC after drug discontinuation, the development of acquired resistance, the dramatic efficacy in patients with Gorlin syndrome, and class-related drug toxicity. Ongoing clinical trials aim to explore the role of vismodegib in the neoadjuvant setting prior to surgery, the potential use of alternate dosing regimens in order to limit chronic adverse events, as well as the identification of patients with BCC that are more likely to respond to this targeted therapy based on genotypic and/or phenotypic characteristics.
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Affiliation(s)
- Clio Dessinioti
- Dermato–Oncology Unit, First Department of Dermatology Venereology, University of Athens, Andreas Sygros Hospital, 5 Dragoumi Str, 16 121, Kaisariani, Athens, Greece
| | - Michaela Plaka
- Dermato–Oncology Unit, First Department of Dermatology Venereology, University of Athens, Andreas Sygros Hospital, 5 Dragoumi Str, 16 121, Kaisariani, Athens, Greece
| | - Alexander J Stratigos
- Dermato–Oncology Unit, First Department of Dermatology Venereology, University of Athens, Andreas Sygros Hospital, 5 Dragoumi Str, 16 121, Kaisariani, Athens, Greece
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Abstract
Advanced basal cell carcinomas are a subset of basal cell carcinomas that can be difficult to treat either due to their local invasiveness, proximity to vital structures, or metastasis. The incidence of all basal cell carcinoma is increasing in the United States, although it is not known whether advanced basal cell carcinomas (aBCCs) are also increasing. Recently, highly targeted therapy based on knowledge of the basal cell carcinoma pathogenesis has become available either commercially or through human clinical trials. These orally available drugs inhibit the Hedgehog signaling pathway, and lead to advanced basal cell carcinoma shrinkage that can enable preservation of adjacent vital organs. In this review, we outline the role of Hedgehog pathway inhibitors as well as other treatment modalities such as excision, radiotherapy and more traditional chemotherapy in treating advanced basal cell carcinomas. We also highlight current gaps in knowledge regarding the use and side effects of this targeted therapy.
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Affiliation(s)
- Shalini V. Mohan
- Department of Dermatology, Stanford University School of Medicine, 450 Broadway St, MC 5334, Pavilion C, 2nd floor, Redwood City, CA 94063 USA
| | - Anne Lynn S. Chang
- Department of Dermatology, Stanford University School of Medicine, 450 Broadway St, MC 5334, Pavilion C, 2nd floor, Redwood City, CA 94063 USA
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Yang W, Neel BG. From an orphan disease to a generalized molecular mechanism: PTPN11 loss-of-function mutations in the pathogenesis of metachondromatosis. Rare Dis 2013; 1:e26657. [PMID: 25003010 PMCID: PMC3927490 DOI: 10.4161/rdis.26657] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 09/30/2013] [Indexed: 12/13/2022] Open
Abstract
Recently, loss-of-function mutations in PTPN11 were linked to the cartilage tumor syndrome metachondromatosis (MC), a rare inherited disorder featuring osteochondromas, endochondromas and skeletal deformation. However, the underlying molecular and cellular mechanism for MC remained incompletely understood. By studying the role of the Src homology-2 domain-containing protein tyrosine phosphatase Shp2 (encoded by mouse Ptpn11) in cathepsin K-expressing cells, we identified a novel cell population in the perichondrial groove of Ranvier. In the absence of Shp2, these cells exhibit elevated Indian hedgehog (Ihh) signaling, proliferate excessively and cause ectopic cartilage formation and tumors. Our findings establish a critical role for a protein-tyrosine phosphatase (PTP) family member, in addition to the well-known roles of receptor tyrosine kinases (RTKs), in cartilage development and homeostasis. However, whether Shp2 deficiency in other epiphyseal chondroid cells and whether signaling pathways in addition to the IHH/Parathyroid Hormone-related Peptide (PTHrP) axis attribute to the formation of enchondromas and osteochondromas remains elusive. Understanding how chondrogenic events are regulated by SHP2 could aid in the development of novel therapeutic approaches to prevent and treat cartilage diseases, such as MC and osteoarthritis (OA).
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Affiliation(s)
- Wentian Yang
- Department of Orthopaedics and COBRE Center for Stem Cell Biology; Brown University Alpert Medical School and Rhode Island Hospital; Providence, RI USA
| | - Benjamin G Neel
- Princess Margaret Cancer Center; University Health Network and Department of Medical Biophysics; University of Toronto; Toronto, ON Canada
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